4-spiro(cyclopropyl)androstenes and process for their production

ABSTRACT

C(-)(-CH3)-CH2-X-),8A-R-1,2,3,4,6,7,8,8A-OCTAHYDRO NOVEL 4-SPIROL(CYCLOPROPYL)ANDROSTENES EMBRACED BY THE FORMULAE:   3-(O=),4,4-(-CH2-CH2-),7,8-(-CH(-)-CH2-CH2-C(-O-R1)(-R2)- &gt;CH2   AND CARBONYL (O=C&lt;). THE COMPOUNDS OF FORMULAE II, III AND V INHIBIT THE ENZYME 3B-HYDROXY STEROID DEHYDROGENASE AND ARE THUS USEFUL IN REGULATING THE PRODUCTION OF GONADAL HORMONES. THE AFORESAID COMPOUNDS OF FORMULAE II, III, AND V ARE CONSEQUENTLY USEFUL IN TREATING MAMMALS, INCLUDING BIRDS IN THOES CONDITIONS WHERE THE FOREGOING PROPERTIES MAKE THE NOVEL COMPOUNDS VALUABLE IN MEDICAL AND VETERINARY PRACTICE.   2-(NC-),3-(O=),4,4-(-CH2-CH2-),7,8-(-CH(-)-CH2-CH2-C(-O-   OCTAHYDRONAPHTHALENE (III) AND   C(-OH)(-R2)-C(-)(-CH3)-CH2-X-),8A-R-1,2,3,4,6,7,8,8A-   2-(HO-CH=),3-(O=),4,4-(-CH2-CH2-),7,8-(-CH(-)-CH2-CH2-   NAPHTHALENE (II) WHEREIN R IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND METHYL; R1 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND ACYL; R2 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, LOWER-ALKYL, LOWER-ALKENYL AND LOWERALKYNYL; AND X IS SELECTED FROM THE GROUP CONSISTING OF METHYLENE   OCTAHYDRONAPHTHALENE     R1)(-R2)-C(-)(-CH3)-CH2-X-),8A-R-1,2,3,4,6,7,8,8A-

' formulae:

United States Pate t C mm.

BRIEF SUMMARY OFTHE INVENTION 4-SPIR0[CYcLoPkggggiggmpos s AND This invention relates to novel 4-spiro[cyclop1- 'y;l]

PROCESS FQR THEIR PRODUCTION androstenes, intermediates and processes for theirproduc; Gilbert A. Youngdale, Portage, Mich., assignor to The 5 Upjohn Company Kalamazoo Mich. i I g I i j I No Drawing. Filed Nov.s, 1972, Sei'. No. 304,849 DETAILED DESCRIPTION OF THE Int. Cl. C07c 173/10 The novel compounds of this invention, intermediates U.S. Cl. 260-23955 R 12 Claims therefor, and processes for" their production areillustra tively represented by the following sequence of formulae ABSTRACT OF THE DISCLOSURE Novel 4-spiro [cyclopropyl] androstenes' embraced by the and wherein R, R R and X have the meanings given above. wherein R is selected ,from the group consisting of hydro- Th compounds f F l 11, I11 d V f this invengen and y 1 is selected from the g p conslsting tion inhibit the production and secretion of ovarian and of hydrogen and acyl; R is selected from the group contesticular steroid hormones including testosterone, es't'ra sisting of hydrogen, loWer-alkyl, lower-alkenyl and lowerdiol, and progesterone. They are thus useful both in t'reat alkynyl; and X is selected from the group consisting of ing animals, including human beings, with pathological methylene production of said hormones (in order to decrease gonadal H steroid production) as well as those with essentially normal production (in order to interrupt gonadal steroid production). Accordingly, compounds of Formula I are useful H in the treatment of prostatic hypertrophy, hirsutism,-'acne,

p hydl.oxymethylene virilization, hyperestrogenism, and in regulation of fertility. The compounds of Formula I also have anti-inflammatory a activity.

The compounds of Formulae II, III and V of this inven- H0 tion, can be prepared and administered to mammals,'=birds and animals, in a wide variety of oral or parenteral-dosage) afld Carbonyl The Compounds of Formulae forms, singly or in admixture with other coacting com- III a V inhibit the enzyme I Y Y stel'old h pounds, in doses of about 1 to 1,000 mg. one to three times" genase and are thus useful in regulating the production of a day, depending on h severity of the condition b i gonadal 110F1110n6$- The aforesaid Compounds of treated and the recipients response to the medication. ulae I, and V are consequently useflfl in treatmg They can be administered with a pharmaceutical carrier mammals, including birds in those Conditions Where the which can be a solid material or a liquid in which the com fOWgOiIlg Properties make novel compounds Valuable pound is dissolved, dispersed or suspended. The solid com in medical and veterinary practice. positions can take theform of tablets, powders, capsules,

pills, or the like, preferably in unit dosage forms for simple can take the form of solutions, emulsions, suspensions,

syrups or elixirs.

In this application the term acy means the acyl radical of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid of from one to twelve carbon atoms inclusive, for example, saturated and unsaturated aliphatic acids and aromatic 'acids, such as acetic, propionic,- butyric, valeric, caproic, caprylic, octanoic, decanoic, dod'ecanoic, tripropylacetic, crotonic, cycyopentylacetic, cyclopentylpropionic, cyclohexylacetic, benzoic, toluic, ethylbenzoic, phenylbutyric, phenylvaleric, cinnamic, naphthaleneacetic, p-butoxyphenylpropionic, phenylpropionic, glutaric, maleic acids, and the like. The term lower-alkyl means an alkylradical, of from one to five carbon atoms, inclusive, such as methyl, ethyl, propyl, butyl, amyl, and isomeric forms thereof. The term loweralkenyl means an alkenyl radical of from two to five carbon atoms, inclusive, such as ethenyl, propenyl, butenyl, pentenyl, and isomeric forms thereof. The term loweralkyny means an alkynyl radical of from two to five carbon atoms, inclusive, such as ethynyl, propynyl, butynyl, pentynyl and isomeric forms thereof.

- .The novel compounds-of Formulae II, III, and V and the intermediates of Formula IV are prepared by the route shown in the above flow diagram, employing the methods and reactions described below. The starting materials embraced by Formula I'are all known in the art.

In-carrying out the process of this invention the starting materials of Formula I are subjected to the following reaction steps:

(1) The selected 17B-hydroxyandrost-4-en-3-one(testosterone) (1) is reacted with a 1,2-dihaloethaue selected from the group consisting of 1,2-dibromoethane, 1,2-dichloroethane and 1,2-diiodoethane in the presence of a base such as sodium amide, potassium amide, or an alkali metal tertiary alkoxide, such as sodium tert. amylate, potassium tert. butoxide and the like, when the base is a sodium or potassium amide the reaction is carried out in the presence of liquid ammonia, although other solvents such as pyridine, dimethylamine, diethylamine, dipropylamine, and the like, can be used. The steroid is conveniently kept in solution by the addition of an inert organic solvent such as tetrahydrofuran, dioxane, di-

ethyl ether, dimethylether and the like. The reaction is advantageously conducted at a temperature below about 0 C. and preferably within the range of from about -30 C. to about -50 C. when liquid ammonia is used as a solvent. The time required for completion I of the reaction ranges from about 1 to about 24 hours depending in part on the selected reactants and the tem' perature employed for carrying out the reaction. The corresponding 17fl-hydroxyspiro[androst-S ene-4,1'-,cy-

clopropan]-3-one (II), thus obtained is recovered from the reaction mixture by conventional methods.

(2) The compounds of Formula II in which R is by drogen are reacted with ethyl formate in accordance with the procedure disclosed in US. Pat. 2,927,933 to obtain the compounds of Formula III. For example, the selected 17fi-hydroxyspiro[androst-5 ene-4,1-cyclopropanJ-B-one (II) is treated with ethyl formate in the presence of an inert organic solvent, preferably a nonpolar, nonprototropic solvent, e.g. benzene, toluene, dioxane, pyridine and the like, and a base, such as an alkali metal alkoxide, e.g. sodium methoxide, sodium tertiary butoxide and the like, or an alkali metal hydride, e.g. sodium hydride and the like to give the corresponding 17/3-hydroxy-2 (hydroxymethylene)spiro[androst-S- ene-4,1'-cyclopropan]-3-one (III).

(3) The compounds of Formula IH are reacted with hydroxylamine hydrochloride in accordance with the procedure disclosed in US. Pat. 3,144,449 to obtain the compounds of Formula IV in which R; is hydrogen. For example, the selected l7fi-hydroxy-2-(hydroxymethylene)spiro[androst-5-ene-4,1'-cyclopropan]-3-one (III) is treated with a solution of an alkali metal acetate, e.g. sodium acetate, in a suitable solvent such as methanol, ethanol, acetic acid, pyridine, tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylformamide, and the like, to obtain the corresponding spiro[androsta-2,5-dieno[2,3-d] isoxazole-4,1'-cyclopropan] l7fi-ol (IV). The reaction can be carried out under reflux conditions until the reaction is complete: a period from about 15 minutes to about 5 hours is generally sufiicient for completion of the reaction, or alternatively, the reaction mixture can be allowed to r'eact'at ambient temperature (e.g. room temperature) for a period of from about 8 to about 24 hours to complete the reaction. The reaction can be carried out under either an anhydrous or aqueous condition.

(4) The compounds of Formula IV are converted to the compounds of Formula V in which R is hydrogen, in accordance with the procedure disclosed in US. Pat. 3,296,255, by cleaving the selected isoxazole (IV) with a strong base, alkali metal alkoxides are preferred and the reaction is best carried out under anhydrous conditions.

The Zm-carbonitriles of Formula V are acidic in nature, having an active hydrogen atom in the 2-position and therefore form salts with strong bases such as alkali metal hydroxides or alkoxides. Thus, in the cleavage of the isoxazole a salt of the Za-carbonitriles (V) is initially produced, and said salt is converted to the free 2dcarbonitrile by acidification. For the purposes of the present invention the salts are the full equivalents of the free Za-carbonitriles (V).

(5) Acyl derivatives of the compounds of Formulae II and V of this invention in which R is hydrogen, are prepared in accordance with methods commonly used for preparing steroid acylates to obtain the corresponding compounds of Formulae II and V of this invention wherein R is acyl. For example, they are prepared by treating the compound in pyridine with excess acid anhydride or acid chloride at about room temperature for 1-24 hours, or by heating the selected compound with a acid anhydride in the presence of pyridine or an alkali earth carbonate such as calcium carbonate. Acylating agents which can be employed are, for example, the anhydrides and chlorides of those acids hereinbefore listed. The excess acylating agent is destroyed by cautious addition of Water to the reaction mixture at 0-10 C. and the product is then isolated by conventional methods.

All of the compounds included within Formulae II through V of the flow-sheet, above, can be isolated from their respective reaction mixtures by conventional means, for example, when a water-miscible solvent is used, by pouring the reaction mixture into water and separating the resulting precipitate by filtration or by extraction with water-immiscible solvents. Additional purification of the products can be accomplished by conventional means, for example, by elution chromatography from an adsorbent column with a suitable solvent such as acetone, ethyl acetate, ether, methylene chloride, Skellysolve B hexanes, and mixtures and combinations of these solvents; also by gradient elution chromatography from an adsorbent column with a suitable mixture of solvents, such as, methylene chloride-Skellysolve B, acetone-Skellysolve B, and the like, and/or by crystallization from a suitable organic solvent or solvents such as those named hereinabove.

The following examples are illustrative of the products and processes of the present invention but are not intended to limit the scope thereof.

Example 1 .17/8-hydroxy-17a-methylspiro [androst-5 cue-4,l-cyclopropan]-3-one (II) To a stirred mixture of sodium amide (prepared from 9.12 g., 0.395 mole of sodium) in 500 ml. of liquid ammonia is added 40 g. (0.132 mole) of l7a-methyltestosterone (I) in 300 ml. of dry tetrahydrofuran during a period of about 45 minutes. The reaction mixture is stirred an additional 15 minutes and then 74.4 g. (0.395 mole) of 1,2-dibromoethane is added during a period of about 35 minutes, followed by 200 ml. of tetrahydrofuran. The mixture is refluxed (Dry Ice condenser) for about 3 hours and then the ammonia is allowed to evaporate overnight. Water (200 ml.) is added cautiously; the tetrahydrofuran is evaporated and then an additional 200 ml. of water is added. The mixture is extracted with methylene chloride. The extract is dried over anhydrous magnesium sulfate and then the methylene chloride is removed by evaporation. The residue thus obtained is dissolved in acetone-methylene chloride and adsorbed on a 2 kg. column of silica gel (packed in 10% acetone-methylene chloride). The column is eluted with 10% acetone-methylene chloride and 200 ml. fractions are collected. Fractions 29-34 are combined and crystallized from acetone-Skellysolve B hexanes to give 3.9 g. of l7'5-hydroxy-l7amethylspiro [androst-5-ene-4,1'-cyclopropan]-3-one (II), M.P. 165-173 C. Fractions 35-47, which are mixtures of product and starting material, are combined with the residue from the evaporation of the solvent from the crystallization filtrate. The material thus obtained is chromatographed as above and the product is crystallized from acetone-Skellysolve B hexanes to give 4.3 g. of 175- hydroxy 17 a methylspiro[androst 5 ene 4,1 cyclopropan]-3-one (II), M.P. 177-179 C. The combined total yield is 8.2 g. (19%) of 175-hydroxy-17u-methylspiro[androst-5-ene-4,4-cyclopropan]-3-one (H); an analytical sample of which recrystallized from ether-Skellysolve B hexanes melts at 175-178 C; [a] CHC1 80; IR (infrared) and NMR (nuclear magnetic responance) spectra support the assigned structure.

Analysis.-Calcd. for C H O (percent): C, 80.44; H, 9.98. Found (percent): C, 80.29; H, 9.82.

Example 2.175-hydroxyspiro[androst-5-ene-4,1'- cyclopropan1-3-one (11) Following the procedure and conditions of Example 1, above, 0.132 mole of testosterone is reacted with 1,2-dibromoethane and the product thus obtained is chromatographed on silica gel to give 175-hydroxyspiro[androst-5- ene-4,1'-cyclopropan]-3-one (II).

In the same manner following the procedure of Example 1, above, other testosterones and 19-nortestosterones of Formula I are likewise converted to the corresponding 175 hydroxyspiro[androst 5 ene 4,1 cyclopropan]- 3-ones and 175-hydroxyspiro[estra-5-ene-4,1'-cyclopropan]-3-ones of Formula II, the following are representative,

17a-ethyltestosterone to obtain 17a-ethyl-175-hydroxyspiro[androst-5-ene-4,1-cyclopropan]-3-one;

17a-propyltestosterone to obtain 17a-propyl-175-hydroxyspiro[androst-5-ene-4,1'-cyclopropan]-3-one;

17a-etheny1testosterone to obtain 17a-ethenyl-175-hydroxyspiro [androst-5-ene-4,1'-cyclopropan]-3-one;

17a-allyltestosterone to obtain 17a-allyl-175-hydroxyspiro[androst-5-ene-4,1'-cyclopropan]-3-one;

17a-ethynyltestosterone to obtain 17a-ethynyl-175-hydroxyspiro[androst-5-ene-4,1'-cyclopropan]-3-one;

17a-propyny1testosterone to obtain 17a-propyny1175- hydroxyspiro [androst-5-ene-4,1'-cyclopropan]-3-one;

115-hydroxytestosterone to obtain 115,175-dihydroxyspiro[androst-5-ene-4,1'-cyclopropan]-3-one;

115-hydroxy-17a-methy1testosterone to obtain 115,175- dihydroxy-lh-methylspiro[androst-5-ene-4,1 cyclopropan]-3-one;

17a-ethyl-115-hydroxytestosterone to obtain 17a-ethy1- 115,175 dihydroxyspiro [androst 5 ene 4,1 cyclopan]-3-one;

115-hydroxy-17a-propyltestosterone to obtain 115,175- dihydroxy 17a propy1spiro[androst- 5 ene 4,1- cyclopropan] -3-one;

17a-ethenyl-115-hydroxytestosterone to obtain 17aethenyl 115,175 dihydroxyspiro[androst-5 ene 4,1- cyclopropan1-3-one;

17u-a1lyl-115-hydroxytestosterone to obtain 17cx-ally1- 115,175 dihydroxyspiro [androst 5 ene 4,1 cyclopropan]-3-one;

17a-ethynyl-115-hydroxytestosterone to obtain 17- ethynyl 115,175 dihydroxyspiro[androst 5 ene 4,1- cyc1opropan1-3-one;

-hydroxy-17a-propynyltestosterone to obtain 115, dihydroxy 17o; propynylspiro[androst 5 ene- 4,1'-cyclopropan]-3-one;

ll-ketotestosterone to obtain 175-hydroxyspiro[androst-5-ene-4,1'-cyclopropane]-3,1l-dione;

11-ketone-17 u-methyltestosterone to obtain 175-hydroxy 17oz methylspiro[androst 5 ene 4,1 cyclopropane]-3-,11-dione;

17a-ethyl-1l-ketotestosterone to obtain 17a-ethyl175- hydroxyspiro[androst 5 ene 4,1 cyclopropane]-3,11- dione;

11-keto-17a-propyltestosterone to obtain 175-hydroxy- 17a propylspiro [androst 5 ene 4,1 cyclopropane]- 3,11-dione;

17m-ethenyl-1l-ketotestosterone to obtain 17a-ethenyl- 175 hydroxyspiro [androst 5 ene 4,1 cyclopropane- 3,11-dione;

17a-allyl-1l-ketotestosterone to obtain 17m-al1yl-175- hydroxyspiro[androst 5 ene 4,1 cyclopropane1- 3,11-dione;

17a-ethynyl-1l-ketotestosterone to obtain Not-ethynyl- 175 hydroxyspiro [androst 5 ene 4,1 cyclopropane]-3,1l-dione;

1l-keto-l7a-propynyltestosterone to obtain 175-hydroxy 17oz propynylspiro[androst 5 ene 4,1 cyclopane]-3,11-dione;

19-nortestosterone to obtain 175-hydroxyspiro[estra-5- ene-4,1-cyclopropan]-3-one;

17a-methyl-19-nortestosterone to obtain 175-hydroxy- 17a-methylspiro [estra-5-ene-4,1-cyclopropan]-3-one;

17a-ethyl-19-nortestosterone to obtain 17a-ethyl-l75- hydroxyspiro[estra-5-ene-4,1-cyclopropan]-3-one; 17a-propyl-19-nortestosterone to obtain 17a-propy1-175- hydroxyspiro [estra-5-ene-4, 1-cycloprop an] -3-one;

17a-ethenyl-19-nortestosterone to obtain 17a-ethenyl- 175-hydroxyspiro [estra-5-ene-4, 1'-cyc1opropan] -3 -one 17u-allyl-19-nortestosterone to obtain 17a-allyl-175- hydroxyspiro [estra-5-ene-4,1'-cyclopropan]-3-one;

17z-ethynyl-19-nortestosterone to obtain Una-ethynyl- 175-hydroxyspiro [estra-5-ene-4,1'-cyclopropan]-3-one;

17a-propynyl-19-nortestosterone to obtain 17u-propynyl 175 hydroxyspiro[estra 5 ene 4,1 cyclopropan]-3-one;

115-hydroxy-19-nortestosterone to obtain 115-,175-dihydroxyspiro [estra-5-ene-4,1-cyclopropan] -3-one;

1l5-hydroxy-l7a-methyl-19-nortestosterone to obtain 115-,175 dihydroxy 17oz methylspiro [estra 5 ene- 4,1-cyclopropan]-3-one;

17u-ethyl 115 hydroxy-19-nortestosterone to obtain 17a-ethy1 115,175 dihydroxyspiro[estra 5 ene-4,1- cyclopropan] -3-one;

115-hydroxy 17 oz propyl-19-nortestosterone to obtain 115,175-dihydroxy 17a propylspiro [estra 5 ene-4,1- cyclopropan]-3-one;

17oz ethenyl-l15-hydroxy-19-nortestosterone to obtain 17a-ethenyl 115,175 dihydroxyspiro[estra-5ene-4,1'- cyclopropan]-3-one;

17a-allyl 115 hydroxy-19-nortestosterone to obtain 17a-ally1 115,175 dihydroxyspiro[estra 5 ene-4,1- cyclopropan]-3-one;

17a-ethynyl-115-hydroxy-19-nortestosterone to obtain 17a ethynyl 115,175 dihydroxyspiro[estra-5-ene-4,1'- cyclopropan]-3-one;

115-hydroxy-17a-propynyl-19-nortestosterone to obtain 115,175 dihydroxy 17o: propynylspiro [estra 5 ene- 4,1'cyclopropan]-3-one;

1l-keto-1'9-nortestosterone to obtain 175-hydroxyspiro- [estra-5-ene-4,1-cyclopropane]-3,1l-dione;

1 1 17a-allyl-175-hydroxyspiro [estra-2,5-dieno [2,3-d]

isoxazole-4,1'-cyc1opropan] -1 1one; 17a-ethynyl-175-hydroxyspiro [estra-2,5-dieno [2,3-d]

isoxazole-4,1'-cyclopropan]-11-one; and 175-hydroxy-17u-propynylspiro[estra-2,5-dieno[2,3-d]

isoxazole-4, 1-cyclopropan] -1 Lone; respectively, and the like.

Example 7.175 hydroxy 17a-methyl-3-oxospiro[androst-5-ene-4,1-cyclopropane] 2a-car-bonitrile (V) A mixture of 9 g. of crude isoxazoles, prepared in Example 5, above, comprising 17u-methylspiro[androsta-2, 5 dieno[2,3-d]isoxazole-4,1-cyclopropan]-175-ol (IV) and 17,17 dimethylspiro[cyclopropane-1,4'-[18]norandrosta-2,5,13-trieno[2,3-d]isoxazole], 70 ml. of dry tetrahydrofuran, and 2.7 g. of powdered sodium methoxide is stirred for about 50 minutes and then heated to reflux for about 5 minutes. The reaction mixture is then cooled and 900 ml. of water is added. The aqueous mixture is then acidified with concentrated hydrochloric acid, cooled in an ice bath and extracted with methylene chloride. The methylene chloride extract is washed with water, dried over anhydrous magnesium sulfate and evaporated to give 8.8 g. of an oil which slowly solidifies. The solid residue thus obtained is dissolved in 10% acetone-methylene chloride and adsorbed on a 1 kg. column of silica gel (packed in 10% acetone-methylene chloride). The column is eluted with 10% acetone-methylene chloride collecting 200 ml. fractions. Fractions 8-10 are combined; the solvent is removed by distillation and the residue thus obtained is crystallized from acetone-Skellysolve B hexanes to give 0.67 g. of 17,17 dimethyl-3-oxospiro[cyclopropane 1,4' [18]norandrosta[5,13]diene-2a-carbonitrile, M.P. 149-153 C.; [a1 CHCl 144; IR and NMR data support the assigned structure.

Analysis.-Calcd. for C23H29N0 (percent): C, 82.34; H, 8.71; N, 4.18. Found (percent): C, 81.73; H, 9.16; N, 4.18.

Fractions -27 are combined, evaporated and the residue crystallized from acetone-Skellysolve B hexanes to give 5.7 g. of 175 hydroxy-17-methyl-3-oxospiro[androst-5- ene 4,1'-cyclopropane]-2a-carbonitrile (V) MP. 207- 209.5 (3.; a sample recrystallized from the same solvent mixture melted at 207209.5 0.; [0G CHCI -49; IR and NMR data support the assigned structure.

Analysis.Calcd. for C H NO (percent): C, 78.14; H, 8.84; N, 3.96. Found (percent): C,77.92; H, 8.98; N, 3.83.

Example 8. l75-hydroxy-3-oxospiro[androst-5-ene-4,1'- cyclopropane] -2a-carbonitrile (V) Following the procedure of Example 7, above, an equivalent amount of spiro[androsta-2,5-dieno[2,3-d]isoxazo1e-4,1'-cyclopropane]-175-ol (IV) is treated with sodium methoxide to obtain 175 hydroxy-3-0xospiro [androst-S- ene-4,1'-cyclopropane]-2u-carbonitrile (V).

In the same manner following the procedure of Example 7, above, other isoxazoles of Formula IV are likewise converted to the corresponding 2a-carbonitriles of Formula V, in which R is hydrogen, for example the compounds prepared and listed in Example 6, above, give:

17 oc-ethyl-175-hydroxy-3-oxospiro androst-5-ene-4, 1'-

cyclopropane] -2a-carbom'trile;

175-hydroxy-3-oxo-17a-propylspiro[androst-5-ene-4,1'-

cycloprop ane] -2 u-carb onitrile;

17a-ethenyl-175-hydroxy-3-oxospiro [androst-5-ene-4, 1'-

cyclopropane] -2a-carbonitrile;

17a-allyl-175-hydroxy-3 -oxospiro [androst-5-ene-4,1'-

cyclo propane] -2a-carb onitrile;

17 a-ethynyl- 175-hydroxy-3 -oxospiro [androst-5-ene-4,1-

cyclopropane] -2a-carbonitrile;

17pt-PIOPYI1Y1- 17 5-hydroxy-3-oxospiro [androst-S -ene-4, 1'-

cyclopropane] -2w-carbonitrile;

1 15,175-dihydroxy-3-oxospiro[androst-5-ene-4,1

cyclopropane] -2a-carb onitrile -hydroxy-3 ,1 1-dioxo-17a-methylspiro [androst-S-ene- 4,1'-cyclopropane] -2a-carbonitrile; 17a-ethy1-175-hydroxy-3, 1 l-dioxospiro] androst-S-ene- 4,1-cyclopropane]-2u-carbonitrile; 175-hydroxy-3,1 l-dioxo- 17 a-propylspiro androst-S -ene 4,1'-cyclopropane]-2a-carbonitrile; 17 ec-ethenyl- 1 75-hydroxy-3 ,1 l-dioxospiro [androst-S-ene- 4,1'-cyclopropane]-2a-carbonitrile;

'17a-allyl-175-hydroxy-3,1 l-dioxospiro [androst-S-ene- 4,1-cyclopropane]-2u-carbonitrile;

17u-ethynyl- 17 5-hydroxy-3 ,1 l-dioxospiro androst-S-ene- 4,1'-cyclopropane]-2ct-carbonitrile;

175-hydroxy-3 ,1 1-di0xo- 17a-propynylspiro [androst-S-ene- 4,1'-cyclopropane]-2a-carbonitrile;

175-hydroXy-3-oxospiro[estra-5-ene-4,1'-cyclopropane]- 2a-car-bonitrile;

17 5-hydroxy-3 -oxo-17o -methylspiro [estra-S-ene- 4,1'-cyclopropane]-2u-carbonitrile;

l7a-ethyl-175-hydroxy-3-oxospiro [estra-S-ene- 4,1'-cyclopropane]-2a-carbonitrile;

17a-propyl-175-hydroxy-3 -oxospiro [estra-S-ene- 4,1-cyclopropane]2a-carbonitrile;

17a-ethenyl- 17 5-hydroxy-3 -oxospiro estra-S-ene- 4,1'-cyclopropane]-2a-carbonitrile;

17a-allyl-175-hydroxy-3-oxospiro [estra-S-ene- 4,1'-cyclopropane]-2ot-carbonitrile;

17a-ethynyl-175-hydroxy-3-oxospiro[estra-S-ene- 4,1'-cyclopropane]-2a-carbonitrile;

17a-propynyl-175-hydroxy-3 -oxospiro [estra-S-ene- 4,1'-cyclopropane]-2u-carbonitrile;

115,175-dihydroxy-3-oxospiro[estra-S-ene- 4,1'-cyclopropane]-2a-carbonitrile;

1 15,175-dihydroxy-3-oxo-17a-rnethylspiro [estra-S-ene- 4,1-cyclopropane]-2a-carbonitrile;

17a-ethy1-115,175-dihydroxy-3-oxospiro[estra-S-ene- 4, 1'-cyclopropane] 2a-carbonitrile;

1 l5, 175-dihydroxy-3 -oxo-17a-propylspiro[estra-S-ene- 4,1'-cyclopropane]-2 x-carbonitrile;

17a-ethenyl-l l5,175-dihydroxy-3-oxospiro[estra-S-ene- 4,1'-cyclopropane]-2ot-carbonitrile;

17u-ally1-l15,175-dihydroxy-3 -oxospiro [estra-5-ene- 4,1-cyclopropane]-2acarbonitrile;

17a-ethnyl-1 15,175-dihydroxy-3-oxospiro[estra-5-ene- 4,1-cyclopropane]-2a-carbonitrile;

1 15,175-dihydroxy-3 -oxo- 17 u-propynylspiro [estra-S -ene- 4, 1-cyclopropane] -2a-carbonitrile;

17a-ally1- 1 15,175-dihydroxy-3 -oxospiro [estra-S-ene- 4,1'-cyclopropane]-2u-carbonitrile;

17 5-hydroxy-3, 1 l-dioxo-17a-methylspiro[estra-S-ene- 4,1'-cyclopropane]-2a-carb0nitrile;

17a-ethy1- 17 5-hydroxy-3,1 1-dioxospiro[estra-5-ene- 4,1-cyclopropane]-2ot-carbonitrile;

175-hydroxy-3 ,1 l-dioxo- 17 a-propylspiro [estra-S -ene- 4, 1'-cyc1opropane] -2a-carb onitrile;

17a-ethenyl- 1 75,-hydroxy-3 ,1 1-dioxospiro[estra-5-ene- 4, 1-cyclopropane] -2a-carbonitrile;

Example 9.-17fi-hydroxy-17a-methylspir0 [androst-S-ene- 4,l'-cyclopropan]-3-one 17-acetate (II) A solution of 1 g. of17fihydroxy-l7a-methylspiro[androst--ene-4,1-cyclopropan]-3-one (II) in 5 ml. of pyridine and 2 ml. of acetic anhydride is heated under nitrogen at about 80 C. for about 16 hours. The solvent is removed on a rotary evaporator and the residue triturated with Skellysolve B hexanes then washed with Skellysolve B hexanes and methanol, and crystallized from acetone- ,Skellysolve B hexanes to give 17p-hydroxy17a-methylspiro[androst-5-ene-4,l'-cyclopropan]-3-0ne 17 acetate :In the same'manner as in Example 9, the l7-propionate, 17 -b utyrate', 17-hexanoate, 17-phe'nylacetate, 17-cinnamate and'other like 17 esters of 17,8-hydroxy-l7oz methylspiro [androst-5-ene-4,1'-cyclopropan]-3-one (II) are prepared by reaction of the 17,8-alcohol (II) with the appropriate acid anhydride or halide. Following the procedure of the immediately preceding paragraph and of Example 9, but substituting other starting materials of Formula II, in which R; is hydrogen and R is alkyl, alkenyl or alkynyl, yields the corresponding 17-acylate of Formula II, in which R is acyl.

Example 10.17;3-hydroxyspiro [androst-5-ene-4, 1'- cyclopropan1-3-one 17-acetate (II) A solution of 1 g. of 17,8-hydroxyspiro [androst-S-ene- 4,1-cyclopropan1-3-one (II) in 5 m1. of pyridine and 2 m1. of acetic anhydride is stirred under nitrogen at room temperature for about 16 hours. The solvent is removed on a rotary evaporator and the residue, triturated with Skellysolve B hexanes then washed with Skellysolve B hexanes and methanol, and crystallized from acetone- Skellysolve B hexanes to give 17B-hydroxyspiro [androst- 5-ene-4, l'-cyclopropan]-3-one '17-acetate (11).

In the same manner as in Example 10, the l7-propionate, 17-butyrate, 17-hexanoate, 17-pheny1acetate, 17-cinnamate and other like 17-esters of 1713-hydroxyspiro[androst-5- ene-4,1-cyclopropan] -3-one (II) are prepared by reaction of the 17B-alcohol (II) with the appropriate acid anhydride or halide. I

Following the procedure of the immediately preceding paragraph and of Example 10, but substituting other starting materials of Formula II, in which R and R are each hydrogen, yields the corresponding l7-acylate of Formula II, in which R is acyl.

Example 11.- 17;9-hydroxy 17a methyl 3 oxospiro- [androst 5 ene' 4,1 cyclopropanej'-- 2a carbonitrile17-acetate (V) a A solution of 1 g.-- of 17p-hydroxy 17oz methyl-3- oxospiro[androst 5 ene 4,1 'cyclopropanl 2acarbonitrile' (V) in 5 ml. of pyridine and 2 ml. of acetic anhydride is heated under nitrogen at about 80 C. for about 16 hours. The solvent is removed on a rotary evaporator and the residue triturated with Skellysolve B hexanes then washed with Skellysolve B hexanes and methanol, and crystallized from acetone-Skellysolve B hexanes to give l7fi-hydroxy 17a methyl 3 oxospiro [androst 5 ene 4,1 cyclopropane] 2oz carbonitrile 17-acetate (V).

In the same manner. as inExample 11, the l7-propionate, 17-butyrate, 17-hexanoate, 17-phenylacetate, 17- cinnamate and other like 17-esters of 17 3-hydroXy-17amethyl-3-oxospiro[androst-S-ene 4,1 -;cyclopro'pane]- Zea-carbonitrile .(V) are prepared by reaction of the 17,3- alcohol (II) 'with the appropriate acidanhydride or, halide.

14 paragraph and of Example "11, but substituting other starting materials of Formula V, 'in which R 'is hydrogen and R is alkyl, alkenyl or alkynyl, yields the corresponding 17-acylate of Formula V in which R is acyl.

Example 12.-17B hydroxy 3 oxospiro[androst 5- ene 4,1 cyclopropane] 2a carbonitrile 17 ace tate (V) A solution of 1 g. of l7fl-hydr oxy-3-oxospiro [androst- S-ene 4,1 cyclopropane] 20c carbonitrile (V) in 5 ml. of pyridine and 2 ml. of acetic anhydride is stirred under nitrogen at room temperature for about 16 hours. The solvent is removed on a rotary evaporator and the residue triturated withISkellysolve B hexanes then washed with Skellysolve B hexanes and methanol, and crystallized from acetone-Skellysolve B hexanes to give 17,3-hydroxy- 3-oxospiro[androst 5 ene 4,1 cyclopropane1-2acarbonitrile 17-acetate (V).

In the same manner as in Example 12, the 17-propionate, 17-butyrate, 17-hexanoate, 17-phenylacetate, 17- cinnamate and other like 17-esters of l7 3-hydroxy-3- oxospiro [androst 5 ene 4,1 cyclopropan]-2u-carbonitrile (V) are prepared by reaction of the 17B-alcohol (V) withthe appropriate acid anhydride or halide.

Following the procedure of the immediately preceding paragraph and of Example 12, but substituting other starting materials of Formula H, in which R and R are each hydrogen,-yields the corresponding 17-acylate of Formula II, in which R is acyl.

I claim 1. A compound selected from the formulae:

wherein R is selected from the group consisting of hydrogen and methyl; R is selected from the group con sisting of hydrogen and'the acyl radical of a hydrocarbon carboxylic acid of 1 to 12 carbon atoms, inclusive, R is selected from the group consisting of hydrogen, lower- V v p p x alkyl of 1 to 5 carbon atoms, inclusive; lower-alkenyl of Following the procedure of the immediately preceding 2 to 5 carbon atoms, inclusive, and lower-alkynyl of 2 15 to '5 carbon atoms, inclusivefand Xis. selected from the group consisting of methylene p-hydroxymethylene.

. o/ and carbonyl (O=C 2. A compound of the formula:

wherein R is selected from the group consisting of hydrogen and methyl; R is selected from the group consisting of hydrogen and the acyl radical of a'hydrocarbon carboxylic acidof 1 to 12 carbon atoms, inclusive. R is selected from the group consisting of hydrogen, loweralkyl of 1 to carbon atoms, inclusive; lower-alkenyl of 2 to 5 carbon atoms, inclusive, and lower-alkynyl of 2 to 5 carbon atoms, inclusive; and X is selected from the group consisting of methylene and carbonyl (O=C 3. 175 hydroxy 17a methylspiro[androst-5-ene-4,1'-

fl-hydroxymethylene cyclopropan1-3-one, the compound of claim 2 wherein R is methyl, R is hydrogen, R is methyl and X is methylene.

4. A compound of the formula:

wherein R is selected from the group consisting of hydrogen and methyl; R is selected from the group consisting of hydrogen, lower-alkyl of l to 5 carbon atoms, inclusive, lower-alkenyl of 2 to 5 carbon atoms, inclusive, and loweralkynyl of 2 to 5 carbon atoms inclusive; and X is selected from the group consisting of methylene and carbonyl"(0= fl-hydroxymethylene 16 5.,17/3 hydroxy -.2 (hydroxymethylenfi). r179:- methylspiro[androst 5-.ene-4,1'-cyclopropan]. 3 -one, the compound of claim 4, whereinR andfR are each methyl and X is methylene. i i

6. A compound of the formiila:

NEG-- and carbonyl (O=C and the alkali metal salts thereof.

7. 17/3 hydroxy 17oz methyl 3 oxospiro[androst- 5 ene 4,1 cyclopropane] 2a carbonitrile, the

compound of claim 6, wherein Ris methyl, R is hydrogen, R is methyl and X is methylene. 8. A compound of the formula:

fl-hydroxymethylene wherein R is selected from the group consisting of hydrogen and methyl; R is selected from the group consisting of hydrogen, lower-alkyl of 1 to 5 carbon atoms, inclusive; lower-alkenyl of 2 to 5 carbon atoms, inclusive, and loweralkynyl of 2 to 5 carbon atoms, inclusive; and X is se+ 0 lected from the group consisting of methylene p-hydroxymethylene I p wherein'R and R are eachmethyl and X is methylene.

10. The process for the production of a compound of the formula:

p-hydroxymethylene 18 and carbonyl (O=C which comprises reacting a compound of the formula:

wherein R, R and X have the meanings given, above, with a 1,2-dihaloethane selected from the group consisting of 1,2 dibromoethane, 1,2 dichloroethane and 1,2 diiodoethane, in the presence of a base selected from the group consisting of sodium amide and potassium amide in liquid ammonia.

11. The process of claim 10, wherein the 1,2-dihaloethane is 1,2-dibromoethane.

12. The process of claim 10, wherein the starting material is 17a-methyltestosterone and the product obtained is hydroxy 17a methylspiro[androst 5 ene- 4,1'-cycl0propan]-3-one.

No references cited.

HENRY A. FRENCH, Primary Examiner US. Cl. X.R. 260397.4, 999

UNITED STATES PATENT OFFICE CERTIFICATE OF CDRRECTION Patent 3 793,308 Dated F b u 19, 1971+ Inventgr(g) Gilbert A. Youngdale It is certified that error appears in the abode-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 5, line 3%, 'H, 9,98" should read H, 9.85 Column 7, line 7, methy lspiro" should read propylspl ro line 22,

(hydroxymethylene-17" should read (hydroxymethylene )-17 line 23, "cycloprpan" should read cyclopropan Column 8, line 5 "propyl" should read propynyl line 65, 'hydroxymethyl)" should read (hydroxymethylene) Column 9, line 12, "diene" should read dieno line 42, dlene" should read dieno line 50, "diene" should read "dieno line 57, "diene" should read -'dleno line 64, "diene" should read dieno line 66, "diene" should read dieno line 68, "diene" should read dleno line 74, "diene" should read dieno Column 11, line 33, "1,4'" should read 154 Column 12, line 59, "ethnyl" should read ethynyl line 65, "17oc-allyl-11B,l75'dihydroxy-Z-oxospiro[estra-5-ene-4,1'-cyclopropane-2a-carbonitrilez" should read 176-hydroxy-5,ll-dioxospiro- [estra-5-ene-4,1'-cyclopropanel-2oL-carbonitrile: Column 15,

l l ne 75, "(0= should read (0=CI:)

Signed and sealed this 5th day of November 1974.

(SEAL) Attest: I

McCOY M. GIBSON JR. c. MARSHALL DANN Attesting Officer Commissioner of Patents FORM Pb-IOSO (1M9) USCOMM-DC 60376-P69 i 11.5. GOVIINIIEIII "nu-ma ornc: nu o-Jn-ssa 

